K+ channelsCheng Long, chenglong_scnu@qq.comSchool of Life Sciences, South China Normal UniversityMarch 20,20121933华南師范大学INIVERSITYSOUTHCHINANORMAL
Cheng Long, chenglong_scnu@qq.com School of Life Sciences, South China Normal University March 20, 2012 K+ channels
The outline...RequiredReadings:YellenG.(2oo2)Thevoltage-gatedpotassiumchannelsandtheirrelatives.Nature419(6902):35-42.ShiehCC,CoghlanM,SullivanJP,GopalakrishnanM.(2ooo)Potassiumchannels:moleculardefects,diseases,andtherapeuticopportunities.PharmacolRev.52:557-594.InternationalUnionofPharmacology(2002).Potassiumchannels,59-63.FurtherReadings:BichetD,HaassFA,JanLY.(2003)Mergingfunctionalstudieswithstructuresof inward-rectifierK+channels.NatureReviewsNeuroscience4:957-967.NiwaN,NerbonneJM.(2010)Moleculardeterminantsofcardiactransientoutwardpotassium current(l(to))expressionandregulation.Mol Cell Cardiol.48(1):12-25
The outline. Required Readings: Yellen G. (2002) The voltage-gated potassium channels and their relatives. Nature 419(6902): 35-42. Shieh CC, Coghlan M, Sullivan JP, Gopalakrishnan M. (2000) Potassium channels: molecular defects, diseases, and therapeutic opportunities. Pharmacol Rev. 52: 557-594. International Union of Pharmacology (2002). Potassium channels, 59-63. Further Readings: Bichet D, Haass FA, Jan LY. (2003) Merging functional studies with structures of inward-rectifier K+ channels. Nature Reviews Neuroscience 4: 957-967. Niwa N, Nerbonne JM. (2010) Molecular determinants of cardiac transient outward potassium current (I(to)) expression and regulation. Mol Cell Cardiol. 48(1): 12-25
The outline...Thisclasswill cover:Types&structureofK+channelsFunction &blockersofK+channelsDiseasesrelatedtoK+channels
The outline. This class will cover: Types & structure of K+ channels Function & blockers of K+ channels Diseases related to K+ channels
IntroductionThe potassium channels are large proteins witha central pore thatpiercesthe cell membraneandallowsonly potassiumionstopassthrough.Inthefieldof cellbiology,potassiumchannelsarethemostwidelydistributed type of ion channel and are found in virtually all livingorganisms.They are found inmost cell typesand controla widevariety of cell functions.They are the largest and most diverse groupofionchannels,representedbysome70knownlociinthemammaliangenome.The first cloned potassium channel gene wasthe Drosophila voltagegated shaker channel, andthiswas rapidly followed bytheidentification of othervoltage-and ligand-gated potassium channelgenes in flies,mammals,and many other organisms.TheKtchannelsareprecisemolecular machinesthat propagateelectrical impulses in the brain, heartand other cell types
Introduction The potassium channels are large proteins with a central pore that pierces the cell membrane and allows only potassium ions to pass through. In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They are found in most cell types and control a wide variety of cell functions. They are the largest and most diverse group of ion channels, represented by some 70 known loci in the mammalian genome. The first cloned potassium channel gene was the Drosophila voltagegated shaker channel, and this was rapidly followed by the identification of other voltage- and ligand-gated potassium channel genes in flies, mammals, and many other organisms. The K+ channels are precise molecular machines that propagate electrical impulses in the brain, heart and other cell types
IntroductionPotassiumchannelspresentinbothexcitableandnonexcitablecells.Members of this channelfamily playcritical roles in cellularsignalingprocesses regulatingneurotransmitterrelease,heartrate,insulinsecretion,neuronal excitability,epithelialelectrolytetransport,smooth muscle contraction,and cell volumeregulation.Over5ohumangenesencodingvariousK+channelshavebeencloned duringthepast decade,andprecisebiophysicalproperties,subunit stoichiometry,channelassemblyandmodulationbysecondmessengerandligandshavebeenaddressedtoalargeextent.The crystalstructureofaK+channelfromStreptomyceslividanshasbecomeavailable
Introduction Potassium channels present in both excitable and nonexcitable cells. Members of this channel family play critical roles in cellular signaling processes regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume regulation. Over 50 human genes encoding various K+ channels have been cloned during the past decade, and precise biophysical properties, subunit stoichiometry, channel assembly and modulation by second messenger and ligands have been addressed to a large extent. The crystal structure of a K+ channel from Streptomyces lividans has become available
AbbreviationsKy,voltage-gatedK+ channel;BKca,largeconductanceCa2+-activatedK+channel;SKca,smallconductanceCa2+-activatedK+channel;EAG,ether-a-go-goK+channel;hERG, human ether-a-go-go-related K+ channel;IKca,intermediate conductance Ca2+-activated K+channel;IKr, cardiac rapid delayed rectifier; IKs, cardiac slow delayed rectifier;IKur, ultrarapid delayed rectifier; IKro,transient outward delayedrectifier;KATp,ATP-sensitiveKt;KCsA,K+channelfromStreptomyceslividans;Kir,inward rectifierK+ channel; Kco,K+ channel opener;M-channel,muscarine-sensitiveK+channel;TWiK,two-pore weak inward rectifier;TREK,two-poreweakinwardrectifier-related K+ channel;TEA,tetraethylammonium;4-AP,4-aminopyridine;MiRP,minKrelated peptide;PHHl,persistenthyperinsulinemichypoglycemiaofinfancy;PS,presenilin;suR,sulfonylureareceptor
Abbreviations Kv , voltage-gated K+ channel; BKCa , large conductance Ca2+-activated K+ channel; SKCa , small conductance Ca2+-activated K+ channel; EAG, ether-a-go-go K+ channel; hERG, human ether-a-go-go-related K+ channel; IKCa , intermediate conductance Ca2+-activated K+ channel; IKr , cardiac rapid delayed rectifier; IKs, cardiac slow delayed rectifier; IKur , ultrarapid delayed rectifier; IKTO , transient outward delayed rectifier; KATP , ATP-sensitive K +; KCsA, K+ channel from Streptomyces lividans; Kir , inward rectifier K+ channel; KCO , K+ channel opener; M-channel, muscarine-sensitive K+ channel; TWIK, two-pore weak inward rectifier; TREK, two-pore weak inward rectifier-related K+ channel; TEA, tetraethylammonium; 4-AP, 4-aminopyridine; MiRP, minK related peptide; PHHI, persistent hyperinsulinemic hypoglycemia of infancy; PS, presenilin; SUR, sulfonylurea receptor
NomenclatureAstandardisednomenclatureforthesix-transmembranedomain(TM),voltage-gatedK+channelgenes-theKnamingsystem-was widely adopted.This nomenclaturewas based ondeduced phylogenetic relationships;channelsthat shared 65%sequence identitybeingassignedtoonesubfamilyAparallelnomenclature-KcN-wasdevelopedbytheHumanGenome Organisation(HUGO).Sincethen,theK+channelsuperfamily of genes has greatly expandedrequiring an updateofthe namingsystem
Nomenclature A standardised nomenclature for the six-transmembrane domain (TM), voltage-gated K+ channel genes – the KV naming system – was widely adopted. This nomenclature was based on deduced phylogenetic relationships; channels that shared 65% sequence identity being assigned to one subfamily. A parallel nomenclature – KCN – was developed by the Human Genome Organisation (HUGO). Since then, the K+ channel superfamily of genes has greatly expanded, requiring an update of the naming system
FeaturesofKtchannelK+channelsselectively conductK+ionsacrossthe cellmembrane along its electrochemical gradient at a rate of 1o6 to108ions/s.Asetofsalientfeatures:a water-filledpermeationpathway(pore)that allowsK+ionsto flowacrossthe cell membrane;a selectivityfilterthat specifiesKtas permeant ionspecies;a gatingmechanismthat servesto switchbetween open and福closed channelconformations.Sincethe first gene encodinga K+ channel was cloned fromDrosophila Shaker mutant, more than 2oo genesencodingavariety of Kt channels have been identified,all containing ahomologousporesegment(S5-S6linker)selectiveforK+ions
Features of K+ channel K+ channels selectively conduct K+ ions across the cell membrane along its electrochemical gradient at a rate of 106 to 108 ions/s. A set of salient features: a water-filled permeation pathway (pore) that allows K+ ions to flow across the cell membrane; a selectivity filter that specifies K+ as permeant ion species; a gating mechanism that serves to switch between open and closed channel conformations. Since the first gene encoding a K+ channel was cloned from Drosophila Shaker mutant, more than 200 genes encoding a variety of K+ channels have been identified, all containing a homologous pore segment (S5-S6 linker) selective for K+ ions
Growth of genes encoding diverse K+ channelsOthersAV250Human200e15010050093‘95'9799
Growth of genes encoding diverse K+ channels
Channel diversity and classification
Channel diversity and classification